Abstract
Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / chemistry
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line, Tumor
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Drug Screening Assays, Antitumor
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Humans
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Indazoles / chemical synthesis*
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Indazoles / chemistry
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Indazoles / pharmacology
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Mice
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Models, Molecular
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Mutation
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Neoplasm Transplantation
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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7-(2,6-difluoro-4-(5-methyl-2,5-diazabicyclo(2.2.1)heptan-2-yl)phenyl)-3-(1H-indazol-4-yl)-2-(pyridin-4-yl)pyrazolo(1,5-a)pyrimidine
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Antineoplastic Agents
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Bridged Bicyclo Compounds, Heterocyclic
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Indazoles
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Pyrazoles
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Pyrimidines
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Proto-Oncogene Proteins B-raf